The incidence of age-related neurological disorders is one of the most intractable barriers to living longer and healthier. Many proteins involved in neurodegeneration, including prion, huntingtin, and APP, are degraded by the proteasome. Importantly, defects in the proteasome have been directly linked to neurodegenerative disorders. Thus, studies of the proteasome-mediated proteolysis will be highly beneficial for delineating the pathogenesis of neurological diseases. We are particularly interested in the degradation of prion proteins. Prion diseases propagate by altering the conformation of a normal protein, PrP, into a pathogenic aggregation-prone protein isoform. Though PrP is efficiently degraded by the proteasome, the exact role of the proteasome in prion-related disorders remains elusive since the mutants defective in prion degradation have not been identified. Recently, we identified components of the proteasome system required for the degradation of a prion protein. The findings provide us the unique entry to define the role of proteolysis in prion diseases. The insights derived from our research will provide significant advancement to our understanding of neurodegeneration and should help find better ways to treat these devastating disorders. [unreadable] [unreadable] [unreadable]